BMP4 and WNT signaling interact to promote mouse tracheal mesenchyme morphogenesis

Tracheobronchomalacia and Complete Tracheal Rings are congenital malformations of the trachea associated with morbidity and mortality for which the etiology remains poorly understood. Epithelial expression of Wls (a cargo receptor mediating Wnt ligand secretion) by tracheal cells is essential for patterning the embryonic mouse trachea's cartilage and muscle. RNA sequencing indicated that Wls differentially modulated the expression of BMP signaling molecules. We tested whether BMP signaling, induced by epithelial Wnt ligands, mediates cartilage formation. Deletion of Bmp4 from respiratory tract mesenchyme impaired tracheal cartilage formation that was replaced by ectopic smooth muscle, recapitulating the phenotype observed after epithelial deletion of Wls in the embryonic trachea. Ectopic muscle was caused in part by anomalous differentiation and proliferation of smooth muscle progenitors rather than tracheal cartilage progenitors. Mesenchymal deletion of Bmp4 impaired expression of Wnt/β-catenin target genes, including targets of WNTsignaling: Notum, and Axin2. In vitro, rBMP4 rescued the expression of Notum in Bmp4 deficient tracheal mesenchymal cells and induced Notum promoter activity via SMAD1/5. RNA sequencing of Bmp4 deficient tracheas identified genes essential for chondrogenesis and muscle development co-regulated by BMP and WNT signaling. During tracheal morphogenesis, WNT signaling induces Bmp4 in mesenchymal progenitors to promote cartilage differentiation and restrict trachealis muscle. In turn, Bmp4 differentially regulates the expression of Wnt/β-catenin targets to attenuate mesenchymal WNT signaling and to further support chondrogenesis.

Aortopexy for Tracheomalacia Via Partial Sternotomy

Tracheomalacia (TM) is a disease that causes the airway obstruction of the tracheal lumen as a result of the structural disorder of the tracheal cartilage. We present a 4-month-old patient who developed ventilator depended TM after repair of esophageal atresia with tracheoesophageal fistula. Aortopexy and intraoperative flexible bronchoscopy were first performed via partial sternotomy in Turkey for this patient. He was weaned from ventilatory support and extubated at the first and discharged at the 8th post-operative day. Partial sternotomy is performed in the supine position, thus it allows for intraoperative flexible bronchoscopy permitting to check for the adequacy of the aortopexy.

Median Sternotomy for Innominate Artery Compression Syndrome and Distal Tracheal Stenosis

We present a case of a premature infant who had an initial diagnosis of an innominate artery compression syndrome. This was approached by a median sternotomy for an aortopexy. However, the patient was found to have a distal tracheal stenosis due to a tracheal cartilage deficiency and was treated by a tracheal resection and primary anastamosis.

3D Printed Biomimetic PCL Scaffold as Framework Interspersed With Collagen for Long Segment Tracheal Replacement

The rapid development of tissue engineering technology has provided new methods for tracheal replacement. However, none of the previously developed biomimetic tracheas exhibit both the anatomy (separated-ring structure) and mechanical behavior (radial rigidity and longitudinal flexibility) mimicking those of native trachea, which greatly restricts their clinical application. Herein, we proposed a biomimetic scaffold with a separated-ring structure: a polycaprolactone (PCL) scaffold with a ring-hollow alternating structure was three-dimensionally printed as a framework, and collagen sponge was embedded in the hollows amid the PCL rings by pouring followed by lyophilization. The biomimetic scaffold exhibited bionic radial rigidity based on compressive tests and longitudinal flexibility based on three-point bending tests. Furthermore, the biomimetic scaffold was recolonized by chondrocytes and developed tracheal cartilage in vitro. In vivo experiments showed substantial deposition of tracheal cartilage and formation of a biomimetic trachea mimicking the native trachea both structurally and mechanically. Finally, a long-segment tracheal replacement experiment in a rabbit model showed that the engineered biomimetic trachea elicited a satisfactory repair outcome. These results highlight the advantage of a biomimetic trachea with a separated-ring structure that mimics the native trachea both structurally and mechanically and demonstrates its promise in repairing long-segment tracheal defects.

Disruption of a hedgehog-foxf1-rspo2 signaling axis leads to tracheomalacia and a loss of sox9+ tracheal chondrocytes

Congenital tracheomalacia, resulting from incomplete tracheal cartilage development, is a relatively common birth defect that severely impairs breathing in neonates. Mutations in the Hedgehog (HH) pathway and downstream Gli transcription factors are associated with tracheomalacia in patients and mouse models; however, the underlying molecular mechanisms are unclear. Using multiple HH/Gli mouse mutants including one that mimics Pallister-Hall Syndrome, we show that excessive Gli repressor activity prevents specification of tracheal chondrocytes. Lineage tracing experiments show that Sox9+ chondrocytes arise from HH-responsive splanchnic mesoderm in the fetal foregut that expresses the transcription factor Foxf1. Disrupted HH/Gli signaling results in 1) loss of Foxf1 which in turn is required to support Sox9+ chondrocyte progenitors and 2) a dramatic reduction in Rspo2, a secreted ligand that potentiates Wnt signaling known to be required for chondrogenesis. These results reveal a HH-Foxf1-Rspo2 signaling axis that governs tracheal cartilage development and informs the etiology of tracheomalacia.

Resection of the arch of cricoid cartilage and circumcision of the tracheal cartilage for subglottic stenosis

Subglottic stenosis is a disease that causes dyspnoea by congenital or acquired stenosis of the cricoid cartilage and trachea. The cause of acquired subglottic stenosis varies. In this case, we present a case of idiopathic subglottic stenosis. Tracheotomies are performed in many cases, but they require long-term insertion of a tracheal cannula and make treatment difficult. In this case study, we performed a tracheoplasty by resection of the arch of cricoid cartilage and circumcision of the tracheal cartilage and implemented a cannula-free observation protocol.